Noam Harel - US grants

Abstract Not Provided.

DESCRIPTION (provided by applicant): Correlation of Functional and Structural Units in Cerebral Cortex This proposal is an expansion of our earlier NIH R21 project that explored the spatial relationship between functional magnetic resonance imaging (fMRI) signals and the underlying neuronal architecture. In a combined high- resolution fMRI and histological study, conducted in the same animal and cortical region, we demonstrated for the first time that tissue fMRI signals peak at cortical layer IV. The spatial specificity of any hemodynamic-based mapping technique is bound by the underlying vascular network;therefore, the spatial relationship between the two is crucial for understanding the mechanisms governing and limiting these mapping techniques. The current understanding of the fMRI contrast mechanism, regarding its vascular origins, is based on numerous assumptions and theoretical modeling, but little experimental validation exists to support or challenge these models. Due to mainly technical limitations, the current knowledge of cerebral vasculature is limited to the large pial surface and capillary level vessels. However, little is known regarding the cluster of intermediate-sized, mainly the intracortical vessels, connecting these two groups and where, arguably, key blood flow regulation takes place. Building on our pervious findings, we will explore the spatial correspondence of fMRI signals with the underlying vascular organization. To accomplish the proposed goal several multimodal developments will be embarked on. A new method for in- vivo visualization and classification (veins and arteries) of cortical vessels will be developed. Utilizing a new and unique ultra high-field (16.4 T / 26 cm) magnet, a high-resolution MRI acquisition schemes combined with ex-vivo micro-CT imaging will enable detailed and accurate 3D modeling of cortical vasculature at resolution approaching the microscopic scale. In addition, analytical tools will be developed to provide morphological description and quantification of the vascular model. Capitalizing on this unique approach, the spatial distribution of stimulus-induced fMRI signal changes will be correlated with the underlying vascular model within the same animal and cortical region. Several hypotheses will be explored with respect to fMRI signals and the cortical vessel morphology such as vessels size and the spatial distributions throughout the tissue. Furthermore, by stimulating only subsets of the neuronal ensemble in primary visual cortex, 3D functional maps of ocular dominance and orientation columns will be generated and correlated with the vascular model. We will investigate whether these functional cortical assemblies are coupled to specific vascular units. The outcome of these studies will be twofold: initially, development of new and unique methodological tools that will provide ways for exploring vascular models. These techniques will be applied to a broad variety of applications that utilize knowledge of the vascular architecture;such application include, but not limited to, fMRI, cerebrovascular diseases, cancer angiogenesis research and models of cerebral thermal regulation all of which will greatly benefit from an accurate vascular model. In the second outcome, neurophysiology research and clinical applications will benefit;with better understanding of the vascular morphology and fMRI mechanism, one can expect the increase in spatial localization and spatial specificity of the fMRI signals to the site of neuronal activity. Clinical applications such as neurosurgery planning, epilepsy and brain tumor resections will all benefit from increased accuracy. Furthermore, if indeed a correlation between functional (neuronal) and structural (vascular) units exist, in the future, it may be used as a diagnostic tool for brain disorders prior to the appearance of any clinical behavioral symptoms. PUBLIC HEALTH RELEVANCE: Functional Magnetic Resonance Imaging (fMRI) is a technique that allows, noninvasively, the localization of active brain regions. Increased neuronal activity in the brain is followed by a small and localized increase in blood flow which can be measured using fMRI. While fMRI has revolutionized the field of human brain research, little is known about the underlying vascular origin of these hemodynamic-based signals. Using a powerful magnet, this study is aims to obtain extremely high-resolution images of cortical vessels, generate a 3-D model of the vascular tree and correlate it with the fMRI signals. The outcome of these studies will greatly enhance our understanding of the vascular network and benefit a variety of research applications including fMRI, cerebrovascular disease, and cancer angiogenesis.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Development of high-resolution diffusion tensor imaging (DTI) and diffusion spectrum imaging (DSI) capabilities in the non-human primate model. The aim of this study will be to 1) validate DTI/DSI fiber tracking algorithms by comparing to histological reconstructions of the fiber tracts. 2) To determine whether high-resolution diffusion-weighted images fiber tracking can image small fiber tracts within the basal ganglia circuits.

Abstract: The University of Minnesota (UMN) Udall Imaging Core, led by Noam Harel, Ph.D. and based at the University of Minnesota's internationally renowned Center for Magnetic Resonance Research (CMRR), will acquire state- of- the-art, high-resolution MRI for all subjects in Projects 1, 2 and 3. The overall goal of the Imaging Core is to use advanced imaging capabilities for direct visualization of anatomical targets for deep brain stimulation (DBS) surgery as well as provide the precise location of individual electrode contacts within the target following implantation. The Imaging Core will combine several cutting edge MRI techniques, including T1 and T2 weighted, susceptibility weighted imaging (SWI) and diffusion weighted imaging (DWI) for tractography to create patient- specific anatomical models of the target region and associated networks. For Projects 1 and 2, PD Parkinson's disease (PD) will be scanned on a 7 T MRI system using tools developed by our team at the CMRR. For Project 3, the non-human primates (NHPs) will be scanned on the newly installed, first of its kind, 10.5 T MRI scanner also at the CMRR. For each PD patient and each NHP, the Imaging Core will acquire high-resolution MRI data prior to implant surgery and a head CT scan after surgery. Images will be fused to provide a comprehensive anatomical model of the DBS target and the precise location of individual DBS contacts within each target. These images will provide unparalleled anatomical characterization specific to each individual. After post- processing analysis, the Imaging Core will create subject-specific computational models estimating the volume of tissue activated by DBS. Subject specific models of anatomical and functional connectivity developed by the Imaging Core will provide data that is vital for the completion of each project in the UMN Udall Center.

PROJECT SUMMARY AND ABSTRACT Essential tremor (ET) is the most common movement disorder in the United States, affecting 4% of all adults over the age of 40. For individuals whose motor symptoms are refractory to medication and significantly impair their daily living, deep brain stimulation (DBS) is considered to be the only bilateral therapeutic option. Despite recent advances in DBS technology, a significant portion of ET patients with DBS implants will receive inadequate tremor control because of poorly placed DBS leads, while others will lose efficacy of the therapy after 1-2 years due in part to inflexible neurostimulator programming options. There is a strong and growing clinical need for implantable DBS lead designs and programming algorithms that can enable clinicians to better sculpt electric fields within the brain, especially in cases where stimulation through a poorly placed DBS lead results in low-threshold side-effects. Our proposed study will integrate high-field magnetic resonance imaging, histological neurotracing of fiber pathways, computational modeling of DBS, and single-cell electrophysiology methods to further develop and experimentally-validate a novel semi-automated machine learning algorithm that facilitates hypothesis-driven determination of subject-specific neurostimulator settings through directional DBS leads. Specifically, we will: 1) identify the neural pathways involved in the reduction of action and postural tremor using directional DBS leads and a novel particle swarm optimization algorithm based on subject-specific anatomy; 2) quantify how tremor-related information is modulated on the single-cell, population, and network levels by therapeutic DBS in a preclinical large-animal model of harmline-induced tremor; and 3) investigate how therapeutic windows (i.e. the threshold difference between postural and action tremor abolishment and side effect emergence) change over time with human DBS therapy targeting one or more pathways within the cerebello-thalamoc-cortical network. Together, this project will (a) experimentally evaluate and translate a novel DBS programming algorithm to human ET patients, (b) provide a much more detailed map of the neural pathways underlying the therapeutic effects of DBS (on postural and action tremor) and side effects of DBS (on dysarthria, paresthesia, ataxia), (c) rigorously investigate how DBS for treating tremor works mechanistically at the single cell and network levels within the brain, and (d) probe the neural pathways involved in the worsening of tremor symptoms for ET patients over time.